The impact of Hepatitis C virus infection on kidney transplantation outcomes: A systematic review of 18 observational studies: The impact of HCV on renal transplantation.

BACKGROUND
Hepatitis C virus (HCV) infection occursin 0% to 51% of dialysis patients, and manyHCV-positive patients are urged to undergo kidney transplantation. However, the outcome of renal transplantation in HCV-positive recipients is unknown.


OBJECTIVES
Our review aimed to address the outcomesof renal transplantation recipients (RTRs)following kidney transplantation.


MATERIALS AND METHODS
We selected studies that used the adjusted relative risk (aRR) and 95% CI of all-cause mortality and graft loss in HCV-positive compared with HCV-negative RTRs as study endpoints. Cox proportional hazard analysis was usedin all studies to calculate the independent effects of HCV infection on RTR outcomes. Sixteen retrospective cohort studies and 2 clinical trials were selected for our review. Sixteen studies were related to patient survival, and 12 examined graft survival.


RESULTS
The combined hazard ratio in HCV-infected recipients was 1.69-fold (1.33-1.97, p < 0.0001) and 1.56 times (1.22-2.004, p < 0.0001) greaterthan that of HCV-negative recipients for mortality and graft loss, respectively.


CONCLUSIONS
Although HCV-infected RTRs have worseoutcomes than HCV-negative RTRs,kidney transplantation is the preferred treatment for patients with HCV infection and end-stage renal disease.


Background
Hepatitis C virus (HCV) infection is a common problem among dialysis patients and kidney transplant recipients (1).The Centers for Disease Control and Prevention (CDC) detects HCV infection by enzyme linked immunosorbent Implication for health policy/practice/research/medical education: HCV infection may negatively interfere on final outcomes of kidney transplantation.We strongly recommend reading this interesting article to all general practitioners, surgeons, nephrologists and urologists.
A risein viral load following immunosuppression in The impact of HCV on renal transplantation HCV-positive kidney transplant recipients was suggested to be a significant cause of pooroutcome (1,4,6,8).Also, viral load and liver deterioration are related (8).Conversely, several surveys did not observe worse outcomes in HCV-positive renal transplant recipients (RTRs) when HCV infection was acquired before kidney transplantation, especially during the first 5-8 years (7).However, a recent study from a US registry evaluated the effect of immunosuppressive regimens on survival in HCV-positive RTRs, demonstrating that antibody induction doesnot adversely affect patient survival (1,7,9).Moreover, cyclosporine (10) and my cophenolat mofetil (MMF) may have protective effects (1,6) and inhibit HCV replication in renal transplant patients with HCV infection.Whether hepatitis virus infected-patients should stay on dialysis or be referred for kidney transplantation remains unknown.

Objectives
We performed a meta-analysis to determine the effects of HCV infection on outcomes in RT patients.

Search strategy
We searched electronic databases, including PubMed, the Cochrane Database of Systematic Reviews, EMBASE, and CINHAL, for studies from Jan 1981 to Jan 2010 to identify those that reported the effect of HCV infection on RTR outcomes.Our keywords included "hepatitis C," "HCV infection," "kidney transplantation," "graft survival," "patients survival," "mortality," "natural history," "outcome," and their synonyms.Two authors independently developed a search strategy to identify randomized trials and cohort studies that investigated the effect of HCV on patients and graft survival after kidney transplantation.To identify additional relevant articles, reference lists from qualitative topic reviews and the identified articles were also searched.Duplicate publications were discarded.We restricted our search to human studies and placed no restrictions on language.

Criteria for inclusion
Two independent reviewers assessed with a standard method each included trial about adult kidney transplant recipients with HCV infection, defined astesting positive for anti-HCV or HCV RNA by polymerase chain reaction (PCR) in serum at the time of enrollment.Also participants were evaluated with regard to patient and kidney outcomes, which were defined as liver-related death and return to dialysis due to HCV infection.Discrepancies were resolved in conference.Other criteria for inclusion were controlled trials and cohort studies that reported patient and graft survival among HCV-infected RTRs.Table 1 shows the characteristics of the studies in this review.Studies that included HCV-infected donors were excluded.Between the trials included in our metaanalysis, there are a few differences in patients and graft outcome (Table 2).Thus, we decided to pool these data for evaluation.

Review questions and endpoints of interest
Our review aimed to answer two specific questions: 1.What is the effect of HCV infection on renal graft survival?
2. What is the effect of HCV infection on renal recipient survival?
All selected studies used the adjusted relative risk (aRR) and 95% CI of all-cause mortality and graft loss in HCVpositive versus -negative RTRs as study endpoints.Cox proportional hazard 5) (we have converted HR to RR with a formula) analysis was usedin all studiesto calculate independent effects of HCV infection on RTR outcomes after adjustments for potentially contributing factors, such as age, gender, follow-up period, type of transplant, diabetes mellitus, post-transplant plasma creatinine, race, duration of dialysis, donor death etiology, and proteinuria.First-generation enzyme-linked immunoadsorbent assay test before 1991, second generation until 1997 and third generation until now were used to detect HCV

Statistical analysis
We pooled outcomes (mortality rates, renal allograft failure), which had been expressed as relative risk (RR) with 95% confidence intervals (CI), using STATA 8.The results of each outcome were analyzed for heterogeneity by Q test (the random effects method of Der Simonian-Laird).Funnel plots, Begg's rank correlation test, and Egger's regression asymmetry test were used to assess the existence of publication bias.The Forest plot was used to demonstrate the details of pooled analysis.Combined hazard ratios were assessed by sensitivity analysis.

Description of Included Trials
The included studies are summarized in Table 1.Follow up duration and adjusted variables for each study shown in table 2 and adjusted relative risk for mortality and graft loss also presented in table 3

Publication bias
For patient and graft survival rates, publication bias was examined using Bagg and Manzumdarand Egger's regression asymmetry, both of which were non-significant [(p = 0.753, p = 0.226; Figure 4) and (p = 0.304, p = 0.55; Figure 5), respectively].Similar results were observed in the funnel plots.

Sensitivity analysis
All eligible studies included in meta-analysis.Because the elimination of each study did not have an impact on the combined hazard ratio, the overall estimation was robust (Figure 6).

Discussion
Hepatitis C infection is a risk factor for graft loss and death in renal transplant recipients (8).Although our report and recent studies have emphasized the detrimental role of hepatitis C in long-term patient and graft survival after renal transplantation (10), several studies have demonstrated that patient and graft survival on-

HR 199
The impact of HCV on renal transplantation HCV infection after renal transplantation arethe same in the shortterm compared withnon-infected renal transplant patients (6).Conversely, kidney transplantation is a better option for HCV-positive ESRD patients versus remaining on dialysis (1).To better examineHCV-positive RTR outcomes, we performed a meta-analysis using observational studies that used adjusted data of all-cause mortality.

Impact on patient survival
Consistent withFabrizi's meta-analysis, the aRR for mortality rate in our study was lower than inother studies (4,8,13,14,17), likely due to the greater sample size, early detection, improvement in management, and exact follow-up.Compared with Fabrizi's meta-analysis, which included 8 articles, our study included 18 articles that comprisedmore than 123,000 RTRs, indicatingthat greaterconsideration has been given to the controversy of HCV-infected RTR outcomes and kidney transplantation in the past5 years.Several studies have demonstrated lower patient and graft survival in HCV-positive RTRs, related in part to associated complications, such as cirrhosis, hepatocellular carcinoma, cardiovascular disease, diabetes mellitus, sepsis, higher PRA, and deceased kidney donation (1,10).

Impact on graft survival:
In our study,the aRR for graft loss was similar to that in Fabrizi's meta-analysis.Although during the first 5-10 years, graft and patient survival was apparently similar between negative and positive HCV-infected RTRs (4), HCV-associated glomerulonephritis, proteinuria, and diabetic nephropathy can progressrapidly to chronic allograft nephropathy (6).

Role of other factors in mortality
It appears that the increased mortality in anti-HCVpositive patients was partially related to mortality dueto causes other than HCV infection.According to a novel risk score for mortality in RTRs (29), the risk score for HCV (1.5) was not more than age above 40 years in comparison to younger than 40 (2.2-6.7),pre-transplant diabetes mellitus (1.8), post-transplant diabetes mellitus (1.5), serum creatinine levels at the first year after transplantation (1.7), and proteinuria greater than 1g during the first year of operation (2.7).In a recent meta-analysis, mortality due to liver complications, such as cirrhosis and hepatocellular carcinoma, among HCV-infected RTRs increased in most studiesthat were included, with anRRof 1.79, compared with HCV-negative recipients (6).In a systematic review, cardiovascular and infectious diseases were also important causes of death in HCV-positive RTRs (6).
Because mortality and graft loss are multifactorial, we used the aRR that had been obtained by the Cox regression model in each study to appraise the isolated influence of HCV infection on patient and graft survival.In contrast to studies that reported a negative impact, the majority of studies that demonstrated a positive impact of transplantation on HCV-infected patient and graft survival rates did not use the Cox regression model; consequently, studies that observed a positive impact or not on HCV-positive patients were excluded from this systematic review and meta-analysis.Although our study and other similar articles on the effect of HCV infection on patient and graft survival did not have any publication bias, it appears that we included only papers with a negative impact (Figure 2, 3).Consistent with previous surveys, we observed that the aRR of all-cause mortality and graft failure was significantly higher for seropositive

Role of immunosuppression in HCV-positive kidney transplant recipients
The progression of liver failure in HCV-positive RTRs following immunosuppression is debated.While previous studies have illustrated a detrimental effect on liver function in these patients (10,11), more recent studies have observed relatively slow development of liver fibrosis in such patients (1).Luan (2008) performed a study using national data and Cox regression analysis to estimate hazard ratios, adjusted for donor, recipient, and transplant variables.A total of 3708 HCV-positive and 75,629 HCV-negative kidney transplant recipients were included, wherein no calcineurin inhibitors (cyclosporine A or tacrolimus) or steroids had a significant impact on patient mortality.Moreover, the use of mycophenolytemofetile (MMF) not only was associated with a significantly reduction in mortality rate, it also had a protective effect (1), despite it sassociation with increased HCV viremia (1).According to another study, HCV replication increases after kidney transplantation, likely due to immunosuppression (1).In contrast, in cultured hepatocytes, cyclosporine A, but not tacrolimus, prevents HCV replication.Notably, more than 50% of HCV-positive kidney transplant recipients who are treated with cyclosporine A have stable liver function and decreased liver fibrosis (1).Nevertheless, in HCV-positive kidney transplant patients, the use of antibody induction has no correlation with viral load (1) and does not have a negative influence on patient survival in these patients (6).It appears that the anti-HCV activity of cyclosporine A differs from its immunosuppressive effects (10).Thus, based on the protective effects of new immunosuppressive drugs, such as MMF and cyclosporine, we hope for greater survival of HCV-positive renal transplant recipients.Yet, controversy still exists regarding the impact of HCV infection on the outcomes of renal transplantation.

Limitations
The majority of articles are not complete; some did not consider Cox regression, and the aRR for patient and graft survival was not reported.Some contributing factors, such as alcohol or drug consumption, were not noted.After renal transplantation, HCV-positive patients have lower patient and graft survival rates compared with HCV-negative patients.However, HCV infection is not a contraindication for renal transplantation; and HCV therapy before transplantation is important to improve the outcome of the patients after transplantation.

Figure 1 .
Figure 1.Summary of literature search and study selection

Figure 2 .Figure 3 .
Figure 2. Hazard ratio in HCV-infected recipients for patient survival

Gentil Govantes et al.
HCV infection after transplantation, con-comitant HBV and HCV infection, occurrence of acute rejection, age at transplantation and time on dialysis, HBeAg positivity, HBsAg positivity, HCV infection after transplantation, age at transplantation and occurrence of acute rejection.

Table 2 .
Follow up and adjusting variables of included articles

for mortality a RR for graft loss Einollahi et al.
a RR a Bruchfeld etal.a Batty et al. a Mahmoud et al.

Table 3 .
Adjusted relative risk for mortality and graft loss Rostami Z et al.The impact of HCV on renal transplantation HCV recipients after kidney transplantation.